The self-medication hypothesis of addictive disorders derives primarily from clinical observations of patients with substance use disorders. Individuals discover that the specific actions or effects of each class of drugs relieve or change a range of painful affect states. Self-medication factors occur in a context of self-regulation vulnerabilities--primarily difficulties in regulating affects, self-esteem, relationships, and self-care. Persons with substance use disorders suffer in the extreme with their feelings, either being overwhelmed with painful affects or seeming not to feel their emotions at all. Substances of abuse help such individuals to relieve painful affects or to experience or control emotions when they are absent or confusing. Diagnostic studies provide evidence that variously supports and fails to support a self-medication hypothesis of addictive disorders. The cause-consequence controversy involving psychopathology and substance use/abuse is reviewed and critiqued. In contrast, clinical observations and empirical studies that focus on painful affects and subjective states of distress more consistently suggest that such states of suffering are important psychological determinants in using, becoming dependent upon, and relapsing to addictive substances. Subjective states of distress and suffering involved in motives to self-medicate with substances of abuse are considered with respect to nicotine dependence and to schizophrenia and posttraumatic stress disorder comorbid with a substance use disorder.

The Self-medication Hypothesis of Substance Use Disorders: A Reconsideration and Recent Applications

Addictive drugs have in common that they are voluntarily self-administered by laboratory animals (usually avidly), and that they enhance the functioning of the reward circuitry of the brain (producing the 'high' that the drug user seeks). The core reward circuitry consists of an 'in-series' circuit linking the ventral tegmental area, nucleus accumbens and ventral pallidum via the medial forebrain bundle. Although originally believed to simply encode the set point of hedonic tone, these circuits are now believed to be functionally far more complex, also encoding attention, expectancy of reward, disconfirmation of reward expectancy, and incentive motivation. 'Hedonic dysregulation' within these circuits may lead to addiction. The 'second-stage' dopaminergic component in this reward circuitry is the crucial addictive-drug-sensitive component. All addictive drugs have in common that they enhance (directly or indirectly or even transsynaptically) dop-aminergic reward synaptic function in the nucleus accumbens. Drug self-administration is regulated by nucleus accumbens dopamine levels, and is done to keep nucleus accumbens dopamine within a specific elevated range (to maintain a desired hedonic level). For some classes of addictive drugs (e.g. opiates), tolerance to the euphoric effects develops with chronic use. Postuse dysphoria then comes to dominate reward circuit hedonic tone, and addicts no longer use drugs to get high, but simply to get back to normal ('get straight'). The brain circuits mediating the pleasurable effects of addictive drugs are anatomically, neurophysiologically and neurochemically different from those mediating physical dependence, and from those mediating craving and relapse. There are important genetic variations in vulnerability to drug addiction, yet environmental factors such as stress and social defeat also alter brain-reward mechanisms in such a manner as to impart vulnerability to addiction. In short, the 'bio-psycho-social' model of etiology holds very well for addiction. Addiction appears to correlate with a hypodopaminergic dysfunctional state within the reward circuitry of the brain. Neuroimaging studies in humans add credence to this hypothesis. Credible evidence also implicates serotonergic, opioid, endocannabinoid, GABAergic and glutamatergic mechanisms in addiction. Critically, drug addiction progresses from occasional recreational use to impulsive use to habitual compulsive use. This correlates with a progression from reward-driven to habit-driven drug-seeking behavior. This behavioral progression correlates with a neuroanatomical progression from ventral striatal (nucleus accumbens) to dorsal striatal control over drug-seeking behavior. The three classical sets of craving and relapse triggers are (a) reexposure to addictive drugs, (b) stress, and (c) reexposure to environmental cues (people, places, things) previously associated with drug-taking behavior. Drug-triggered relapse involves the nucleus accumbens and the neurotransmitter dopamine. Stress-triggered relapse involves (a) the central nucleus of the amygdala, the bed nucleus of the stria terminalis, and the neurotransmitter corticotrophin-releasing factor, and (b) the lateral tegmental noradrenergic nuclei of the brain stem and the neurotransmitter norepinephrine. Cue-triggered relapse involves the basolateral nucleus of the amygdala, the hippocampus and the neurotransmitter glutamate. Knowledge of the neuroanatomy, neurophysiology, neurochemistry and neuropharmacology of addictive drug action in the brain is currently producing a variety of strategies for pharmacotherapeutic treatment of drug addiction, some of which appear promising.

Addiction and brain reward and antireward pathways.

Both chronic pain and prescription opioid abuse are prevalent and continue to exact a heavy toll on patients, physicians, and society. Individuals with chronic pain and co-occurring substance use disorders and/or mental health disorders, are at a higher risk for misuse of prescribed opioids. Opioid abuse and misuse occurs for a variety of reasons, including self medication, use for reward, compulsive use because of addiction, and diversion for profit. Treatment approaches that balance treating chronic pain while minimizing risks for opioid abuse, misuse, and diversion are much needed. The use of chronic opioid therapy for chronic noncancer pain has increased dramatically in the past 2 decades in conjunction with a marked increase in the abuse of prescribed opioids and accidental opioid overdoses. Consequently, a validated screening instrument that provides an effective and rational method of selecting patients for opioid therapy, predicting risk, and identifying problems once they arise could be of enormous benefit. Such an instrument could potentially curb the risk of iatrogenic addiction. Although several screening instruments and strategies have been introduced in the past decade, there is no single test or instrument that can reliably and accurately predict patients who are not suitable for opioid therapy or identify those who need increased vigilance or monitoring during therapy. At present screening for opioid abuse includes assessment of premorbid and comorbid substance abuse; assessment of aberrant drug-related behaviors; risk factor stratification; and utilization of opioid screening tools. Multiple opioid assessment screening tools and instruments have been developed by various authors. In addition, urine drug testing, monitoring of prescribing practices, prescription monitoring programs, opioid treatment agreements, and utilization of universal precautions are essential. Presently, a combination of strategies is recommended to stratify risk, identify and understand aberrant drug related behaviors, and tailor treatments accordingly. This manuscript will review the current state of knowledge regarding the growing problem of opioid abuse and misuse; known risk factors; and methods of predicting, assessing, monitoring, and addressing opioid abuse and misuse in patients with chronic noncancer pain.

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Prescription Opioid Abuse in Chronic Pain: A Review of Opioid Abuse Predictors and Strategies to Curb Opioid Abuse

Prevalence of comorbid substance use in schizophrenia spectrum disorders in community and clinical settings, 1990-2017: Systematic review and meta-analysis.

https://www.cell.com/trends/pharmacological-sciences/pdf/S0165-6147(11)00158-1.pdf

Cytochrome P450 enzymes in the brain: emerging evidence of biological significance.

The link between schizophrenia and substance use disorder: A unifying hypothesis

Schizophrenia is a heterogenous and severe neuropsychiatric disorder that affects nearly 1% of the population worldwide. Antipsychotic drugs are the mainstay of treatment, but not all patients with schizophrenia respond to treatment with these agents. Clozapine, the first atypical antipsychotic, is a highly effective medication for patients with schizophrenia who do not respond to other antipsychotics. Although clozapine tends not to produce extrapyramidal symptoms, other side effects of the drug (e.g., agranulocytosis, myocarditis, seizures) limit its widespread use. This chapter reviews clozapine's unique clinical effects and unusual pharmacological profile. In addition to its effects in treatment-resistant schizophrenia, clozapine has been shown to decrease suicidality, which occurs at an increased rate in patients with schizophrenia. Still preliminary, but consistent data, also suggest that clozapine limits substance use in these patients, an important effect since substance use disorders are common in patients with schizophrenia and are associated with a poor outcome, including an increased risk for suicide and poor response to treatment. We have suggested, from animal studies, that clozapine's apparent ability to limit substance use may occur through its actions as a weak dopamine D2 receptor antagonist, a potent norepinephrine α-2 receptor antagonist and a norepinephrine reuptake inhibitor. Using animal models, we have built combinations of agents toward creation of safer clozapine-like drugs to reduce substance use in these patients. Future research into the mechanisms of action of clozapine toward the development of safe clozapine-like agents is of great public health importance.

/pdf/unique-effects-of-clozapine-a-pharmacological-perspective-2pwqqosjun.pdf

Jibran Y. Khokhar

Papers

The link between schizophrenia and substance use disorder: A unifying hypothesis

Unique Effects of Clozapine: A Pharmacological Perspective.

Rat brain CYP2B-enzymatic activation of chlorpyrifos to the oxon mediates cholinergic neurotoxicity.

Adolescent neurodevelopment and substance use: Receptor expression and behavioral consequences

Drug metabolism within the brain changes drug response: selective manipulation of brain CYP2B alters propofol effects.